We propose to develop a novel approach for the treatment of invasive and metastatic cancers based on novel therapeutic monoclonal antibodies (mAb). The targets are the cell-surface proteases ADAM10 and ADAM17, which are key drivers of tumor growth, invasion, drug resistance and metastasis. ADAM10 is activated in most cancers and, in turn, activates oncogenic pathways, including EGFR/ErbB, Notch, and Eph, as well as those underlying resistance to platinum and taxane-based chemotherapies, and to targeted anti-EGFR and anti-angiogenic therapies. While ADAMs are well-validated anti-tumor targets, inhibitors against their catalytic active sites failed clinical trials due to lack of specficity and efficacy. Likewise, clinically pursued inhibitors of downstream targets, such as ?-secretase, suffer from similar limitations due to side effects on non-tumor cells. We have identified a novel intervention strategy based on a mAb targeting an essential for activity, non- catalytic substrate-recognition ADAM10 pocket. This mAb selectively recognizes an active ADAM10 population over-represented in tumors, and inhibits oncogenic signaling and tumor growth, but does not show dose-limiting toxicities in animals. Our approach provides three significant advantages over the alternatives: i) It targets multiple oncogenic pathways at the same time, therefore patients are much less likely to develop resistance to treatment; ii) Unlike chemotherapy and other approaches, it targets not only rapidly dividing tumor cells, but also tumor stem cells, which do not aggressively divide; iii) It selectively targets a tumor-specific conformation of an essential for tumor growth and metastasis protein, thus not affecting non-tumor cells. In this R21 application we propose to investigate the molecular mechanism of action of the antibody, to further characterize its therapeutic potential, and to generate and characterize mAbs against the substrate-binding domain of ADAM17. Although this study involves considerable risk, its outcome could provide a highly effective and novel intervention approach for the cure of invasive and metastatic cancer.